Bupropion hydrochloride

Description

Bupropion hydrochloride, an antidepressant of the aminoketone class, is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitor, or other known antidepressant agents. It is designated as (±)-1-(3-chlorophenyl)-2-(1,1-dimethylethyl)amino-1-propanone hydrochloride. The molecular weight is 276.2, and the molecular formula is C13H18ClNO•HCl. Bupropion hydrochloride powder is white, crystalline, and highly soluble in water. It has a bitter taste and produces the sensation of local anesthesia on the oral mucosa.

Bupropion hydrochloride tablets USP are supplied for oral administration as 75 mg (light orange) and 100 mg (light yellow) film-coated tablets. Each 75 mg tablet contains microcrystalline cellulose, hypromellose, low-substituted hydroxypropyl cellulose, magnesium stearate, titanium dioxide, ethyl cellulose, triacetin, iron oxide yellow, iron oxide red, and FD&C Red No. 40. Each 100 mg tablet contains microcrystalline cellulose, hypromellose, low-substituted hydroxypropyl cellulose, magnesium stearate, titanium dioxide, ethyl cellulose, and triacetin, along with iron oxide yellow.

Uses and Indications

Bupropion hydrochloride tablets are indicated for the treatment of major depressive disorder (MDD).

There are no teratogenic or nonteratogenic effects associated with the use of this medication.

Dosage and Administration

The recommended starting dose for the medication is 200 mg per day, administered as 100 mg twice daily. To minimize the risk of seizures, healthcare professionals should increase the dose gradually. After an initial period of 3 days, the dose may be escalated to 300 mg per day, given as 100 mg three times daily, ensuring that there is an interval of at least 6 hours between doses. The usual target dose is 300 mg per day, maintained as 100 mg three times daily.

The maximum allowable dose is 450 mg per day, which can be administered as 150 mg three times daily. It is essential for healthcare providers to periodically reassess the patient's dose and the necessity for ongoing maintenance treatment.

For patients with moderate to severe hepatic impairment, the recommended dose is 75 mg once daily. In cases of mild hepatic impairment, consideration should be given to reducing the dose and/or frequency of administration. Similarly, for patients with renal impairment, a reduction in dose and/or frequency may be warranted based on individual patient assessment.

Contraindications

Use of bupropion hydrochloride tablets is contraindicated in the following situations:

• Patients with a seizure disorder, due to the increased risk of seizures.

• Individuals with a current or prior diagnosis of bulimia or anorexia nervosa, as these conditions may increase the risk of adverse effects.

• Patients who have abruptly discontinued alcohol, benzodiazepines, barbiturates, or antiepileptic drugs, as this may precipitate seizures.

• Concurrent use with Monoamine Oxidase Inhibitors (MAOIs) intended for psychiatric disorders is contraindicated. Bupropion hydrochloride tablets should not be used within 14 days of stopping an MAOI, nor should an MAOI be initiated within 14 days of stopping bupropion hydrochloride tablets. Additionally, bupropion should not be started in patients receiving linezolid or intravenous methylene blue.

• Individuals with known hypersensitivity to bupropion or any of the other ingredients in bupropion hydrochloride tablets.

Warnings and Precautions

Patients undergoing smoking cessation with bupropion should be closely monitored for neuropsychiatric adverse events. Postmarketing reports have indicated serious or clinically significant reactions, including mood changes (such as depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, panic, as well as suicidal ideation, suicide attempts, and completed suicides. Healthcare professionals are advised to observe these patients for the emergence of such symptoms and to instruct them to discontinue bupropion and seek immediate medical attention if they experience any of these adverse events.

The risk of seizures associated with bupropion is dose-related. To minimize this risk, it is recommended that the dosage be gradually increased, with a maximum daily limit of 450 mg. Should a seizure occur, bupropion must be discontinued immediately.

Bupropion hydrochloride tablets have the potential to elevate blood pressure. Therefore, it is essential to monitor blood pressure prior to initiating treatment and periodically throughout the course of therapy.

Patients with a history of bipolar disorder should be screened prior to treatment, as bupropion may activate mania or hypomania. Continuous monitoring for these symptoms is also recommended.

In addition, patients should be informed about the risk of psychosis and other neuropsychiatric reactions. They should be instructed to contact a healthcare professional if they experience any such reactions.

Angle-closure glaucoma has been reported in patients with untreated anatomically narrow angles who are treated with antidepressants, including bupropion.

There is a warning regarding the increased risk of suicidal thoughts and behaviors in children, adolescents, and young adults taking antidepressants. Healthcare providers should monitor these patients for any worsening or emergence of suicidal thoughts and behaviors.

To ensure patient safety, it is crucial to monitor blood pressure before starting treatment and periodically during treatment. Patients should be advised to discontinue bupropion and contact their healthcare provider if they experience neuropsychiatric adverse events or if a seizure occurs.

Side Effects

Patients receiving bupropion hydrochloride tablets may experience a range of adverse reactions, which can be categorized by seriousness and frequency.

Most common adverse reactions observed in clinical trials include agitation, dry mouth, constipation, headache or migraine, nausea or vomiting, dizziness, excessive sweating, tremor, insomnia, blurred vision, tachycardia, confusion, rash, hostility, cardiac arrhythmias, and auditory disturbances.

Serious warnings include an increased risk of suicidal thoughts and behaviors, particularly in children, adolescents, and young adults taking antidepressants. It is essential to monitor these patients for any worsening or emergence of suicidal thoughts and behaviors.

Neuropsychiatric adverse events have been reported during smoking cessation, including changes in mood (such as depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, panic, suicidal ideation, suicide attempts, and completed suicides.

There is a dose-related risk of seizures associated with bupropion hydrochloride. To minimize this risk, it is recommended to gradually increase the dose and limit the daily dose to 450 mg. Discontinuation of the medication is advised if a seizure occurs. Additionally, bupropion hydrochloride tablets can increase blood pressure; therefore, blood pressure should be monitored before and periodically during treatment.

Patients with a history of bipolar disorder should be screened and monitored for activation of mania or hypomania. Instructing patients to contact a healthcare professional if they experience psychosis or other neuropsychiatric reactions is also advised.

Angle-closure glaucoma has been reported in patients with untreated anatomically narrow angles who are treated with antidepressants.

Other important considerations include the risk of seizures in patients with a seizure disorder, current or prior diagnosis of bulimia or anorexia nervosa, and the abrupt discontinuation of alcohol, benzodiazepines, barbiturates, or antiepileptic drugs. Bupropion hydrochloride should not be used in conjunction with monoamine oxidase inhibitors (MAOIs) intended for psychiatric disorders or within 14 days of stopping treatment with either bupropion or an MAOI.

In cases of overdose, seizures were reported in approximately one-third of all cases. Other serious reactions associated with bupropion overdose include hallucinations, loss of consciousness, mental status changes, sinus tachycardia, ECG changes (including conduction disturbances and arrhythmias), clonus, myoclonus, hyperreflexia, fever, muscle rigidity, rhabdomyolysis, hypotension, stupor, coma, and respiratory failure. Deaths have been reported in patients who ingested large doses of bupropion, often preceded by multiple uncontrolled seizures, bradycardia, cardiac failure, and cardiac arrest.

Drug Interactions

CYP2B6 inducers, such as ritonavir, lopinavir, efavirenz, carbamazepine, phenobarbital, and phenytoin, may necessitate an increase in the dosage of bupropion based on clinical response, without exceeding the maximum recommended dose.

Bupropion is a known inhibitor of CYP2D6, which can lead to elevated concentrations of certain medications. This includes antidepressants like venlafaxine and nortriptyline, antipsychotics such as haloperidol, beta-blockers including metoprolol, and Type 1C antiarrhythmics like propafenone.

Monitoring of digoxin levels is recommended, as bupropion may reduce plasma concentrations of digoxin.

Caution is warranted when bupropion is used in conjunction with drugs that lower the seizure threshold, due to an increased risk of seizures. Additionally, the concomitant use of bupropion with dopaminergic medications, such as levodopa and amantadine, may result in central nervous system toxicity.

There is an increased risk of hypertensive reactions when bupropion is administered alongside monoamine oxidase inhibitors (MAOIs).

It is also important to note that bupropion can lead to false-positive results for amphetamines in urine drug tests.

Packaging & NDC

The table below lists all NDC Code configurations of Bupropion Hydrochloride, the U.S. brand-name prescription product. Columns show Packaging, Formulation Type, and Active Ingredient Strength.

Pediatric Use

Safety and effectiveness in the pediatric population have not been established. Healthcare professionals should refer to the Boxed Warning and Warnings and Precautions (5.1) for additional information regarding the use of this medication in children and adolescents. Caution is advised when considering treatment options for pediatric patients.

Geriatric Use

Clinical trials involving bupropion sustained-release tablets included approximately 6,000 subjects, of which 275 were aged 65 years and older, and 47 were aged 75 years and older. Additionally, several hundred subjects aged 65 years and older participated in trials with the immediate-release formulation of bupropion.

No overall differences in safety or effectiveness were observed between elderly patients and younger subjects. However, while clinical experience has not identified significant differences in responses, it is important to note that greater sensitivity in some older individuals cannot be ruled out.

Bupropion is extensively metabolized in the liver to active metabolites, which are subsequently metabolized and excreted by the kidneys. Given that elderly patients are more likely to have decreased renal function, the risk of adverse reactions may be heightened in this population. Therefore, it is advisable to consider renal function when selecting doses for geriatric patients, and monitoring of renal function may be beneficial to ensure safety and efficacy.

Pregnancy

There is an independent pregnancy exposure registry that monitors pregnancy outcomes in women exposed to any antidepressants during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Antidepressants at 1-844-405-6185 or visiting online at National Pregnancy Registry for AntidepressantsNational Pregnancy Registry for Antidepressants.

Data from epidemiological studies of pregnant women exposed to bupropion in the first trimester have not identified an increased risk of congenital malformations overall. However, there are risks to the mother associated with untreated depression during pregnancy. Animal studies indicate that when bupropion was administered to pregnant rats during organogenesis, there was no evidence of fetal malformations at doses up to approximately 10 times the maximum recommended human dose (MRHD) of 450 mg/day. Conversely, when given to pregnant rabbits during organogenesis, non-dose-related increases in the incidence of fetal malformations and skeletal variations were observed at doses approximately equal to the MRHD and greater. Additionally, decreased fetal weights were noted at doses twice the MRHD and higher.

The estimated background risk for major birth defects and miscarriage is unknown for the indicated population; however, all pregnancies carry a background risk of birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

A prospective, longitudinal study followed 201 pregnant women with a history of major depressive disorder who were euthymic and taking antidepressants at the beginning of pregnancy. The findings indicated that women who discontinued antidepressants during pregnancy were more likely to experience a relapse of major depression compared to those who continued their medication. Therefore, it is essential to consider the risks to the mother of untreated depression and the potential effects on the fetus when discontinuing or changing treatment with antidepressant medications during pregnancy and postpartum.

Data from the international bupropion Pregnancy Registry, which included 675 first trimester exposures, and a retrospective cohort study using the United Healthcare database with 1,213 first trimester exposures did not show an increased risk for malformations overall. Although the Registry was not designed to evaluate specific defects, it suggested a possible increase in cardiac malformations. The prospectively observed rate of cardiovascular malformations in pregnancies with exposure to bupropion in the first trimester was 1.3%, which is similar to the background rate of approximately 1%. However, study findings regarding bupropion exposure during the first trimester and the risk for left ventricular outflow tract obstruction (LVOTO) and ventricular septal defect (VSD) are inconsistent and do not allow for definitive conclusions regarding a possible association.

In animal studies, bupropion was administered orally to pregnant rats and rabbits during organogenesis at doses of up to 450 mg/kg/day and 150 mg/kg/day, respectively. There was no evidence of fetal malformations in rats, while in rabbits, non-dose-related increases in fetal malformations and skeletal variations were observed at the lowest tested dose (25 mg/kg/day) and greater. Decreased fetal weights were noted at doses of 50 mg/kg/day and higher, with no maternal toxicity evident at doses of 50 mg/kg/day or less. In a pre- and postnatal development study, bupropion administered to pregnant rats at doses of up to 150 mg/kg/day from embryonic implantation through lactation had no effect on pup growth or development.

Lactation

Data from published literature report the presence of bupropion and its metabolites in human milk. In a lactation study involving 10 women, levels of orally dosed bupropion and its active metabolites were measured in expressed milk. The average daily infant exposure, assuming a daily consumption of 150 mL/kg, to bupropion and its active metabolites was found to be 2% of the maternal weight-adjusted dose.

Currently, there are no data available regarding the effects of bupropion or its metabolites on milk production. Limited data from postmarketing reports have not identified a clear association of adverse reactions in breastfed infants. However, it is important to note that postmarketing reports have described seizures in breastfed infants, although the relationship between bupropion exposure and these seizures remains unclear.

When considering the use of bupropion hydrochloride in lactating mothers, the developmental and health benefits of breastfeeding should be weighed against the mother's clinical need for the medication and any potential adverse effects on the breastfed child from bupropion hydrochloride or from the underlying maternal condition.

Renal Impairment

Patients with renal impairment have not been specifically addressed in the available data regarding dosage adjustments, special monitoring, or safety considerations. Therefore, healthcare professionals should exercise caution when prescribing this medication to patients with reduced kidney function, as the lack of information necessitates careful clinical judgment and monitoring.

Hepatic Impairment

Patients with hepatic impairment have not been specifically studied in relation to the use of this medication. Consequently, there are no established dosage adjustments, special monitoring requirements, or precautions for individuals with compromised liver function. It is recommended that healthcare providers exercise caution when prescribing this medication to patients with hepatic impairment, given the lack of data on its safety and efficacy in this population. Regular monitoring of liver function may be prudent in these cases, although specific parameters are not defined in the available information.

Overdosage

Overdoses of bupropion have been documented, with instances involving doses of 30 grams or more. In approximately one-third of these cases, seizures have been reported, highlighting the potential neurological risks associated with excessive intake.

Serious adverse reactions stemming from bupropion overdose may include hallucinations, loss of consciousness, alterations in mental status, and respiratory failure. These symptoms are particularly pronounced in cases involving multiple drug overdoses, which can complicate the clinical picture and necessitate more intensive management.

Fatalities linked to bupropion overdose have also been recorded. These tragic outcomes often arise from a combination of factors, including multiple uncontrolled seizures, bradycardia, cardiac failure, and cardiac arrest. Such severe manifestations underscore the critical nature of prompt and effective intervention.

Currently, there are no known antidotes for bupropion overdose. Therefore, the cornerstone of management involves supportive care and vigilant medical supervision. Healthcare professionals are advised to monitor the patient closely and provide symptomatic treatment as necessary.

In the event of a suspected overdose, it is imperative to consult a Certified Poison Control Center for expert guidance. Healthcare providers can reach the Poison Control Center by calling 1-800-222-1222 or visiting www.poison.org for additional resources and support.

Nonclinical Toxicology

No teratogenic effects were observed in the studies conducted. In terms of non-teratogenic effects, administration of bupropion at oral doses up to 300 mg/kg/day to rats, which is approximately six times the maximum recommended human dose (MRHD) on a mg/m² basis, did not adversely affect male or female fertility. This treatment was given to females prior to mating and continued either through Day 13 of gestation or through lactation, while males were treated for 60 days prior to and during mating. However, doses of 200 mg/kg/day or greater, approximately four times the MRHD on a mg/m² basis, resulted in transient ataxia or behavioral changes in adult female rats. Importantly, there were no adverse effects noted on fertility, reproduction, or the growth and development of male or female offspring.

Lifetime carcinogenicity studies were conducted in rats and mice with bupropion doses reaching up to 300 mg/kg/day and 150 mg/kg/day, respectively, which correspond to approximately six and two times the MRHD on a mg/m² basis. In the rat study, an increase in nodular proliferative lesions of the liver was observed at doses ranging from 100 to 300 mg/kg/day, approximately two to six times the MRHD on a mg/m² basis; lower doses were not evaluated. The potential for these lesions to serve as precursors to liver neoplasms remains unresolved. Conversely, similar liver lesions were not detected in the mouse study, and no increase in malignant tumors of the liver or other organs was noted in either study.

Bupropion demonstrated a positive response in the Ames bacterial mutagenicity assay, with a mutation rate that was two to three times higher than the control in two out of five strains tested. Additionally, an increase in chromosomal aberrations was reported in one of three in vivo rat bone marrow cytogenetic studies.

Postmarketing Experience

Some patients have reported experiencing changes in mood, including depression and mania, as well as psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, and panic. Suicidal ideation and suicide attempts have also been noted in individuals attempting to quit smoking while taking bupropion.

New or exacerbated mental health issues, such as changes in behavior or thinking, aggression, hostility, agitation, depression, or suicidal thoughts or actions, have been documented. These symptoms have been observed in some individuals upon initiation of bupropion therapy, while others developed them after several weeks of treatment or following discontinuation of the medication. The incidence of these symptoms appears to be higher in individuals with a prior history of mental health disorders compared to those without such a history.

Patients experiencing a seizure while on bupropion hydrochloride tablets are advised to discontinue use immediately and contact their healthcare provider. Re-administration of bupropion hydrochloride tablets is contraindicated in individuals who have had a seizure.

Instances of severe hypertension have been reported in some patients taking bupropion hydrochloride tablets, with an increased risk noted in those concurrently using nicotine replacement therapy, such as nicotine patches, to aid in smoking cessation.

Unusual thoughts or behaviors, including delusions, hallucinations, paranoia, or confusion, have been reported by some patients during treatment with bupropion hydrochloride tablets. Affected individuals are encouraged to contact their healthcare provider if such symptoms occur.

Severe allergic reactions have also been documented. Patients should discontinue bupropion hydrochloride tablets and seek immediate medical attention if they experience symptoms such as rash, itching, hives, fever, swollen lymph glands, painful sores in the mouth or around the eyes, swelling of the lips or tongue, chest pain, or difficulty breathing.

Patient Counseling

Patients should be advised to read the FDA-approved patient labeling (Medication Guide) thoroughly. It is important to instruct patients, their families, and/or caregivers to remain vigilant for the emergence of symptoms such as anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, and other unusual changes in behavior, as well as worsening depression and suicidal ideation. These symptoms may occur, particularly during the initial stages of antidepressant treatment or when the dosage is adjusted.

Families and caregivers should be encouraged to monitor patients on a daily basis for any abrupt changes in behavior, as these can be significant. Any severe, sudden, or previously unreported symptoms should be communicated to the patient’s prescriber or healthcare professional promptly.

Patients should be informed that some individuals may experience mood changes, including depression and mania, as well as psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, and panic, along with suicidal thoughts when attempting to quit smoking while taking bupropion. If patients experience any of these symptoms, they should discontinue bupropion and contact a healthcare professional immediately.

Education on hypersensitivity symptoms is essential, and patients should be instructed to discontinue bupropion hydrochloride tablets if they experience a severe allergic reaction. Additionally, patients must be advised to stop taking bupropion hydrochloride tablets and not to restart them if they experience a seizure during treatment.

Patients should be cautioned that excessive use or abrupt discontinuation of alcohol, benzodiazepines, antiepileptic drugs, or sedatives/hypnotics can increase the risk of seizures, and they should minimize or avoid alcohol consumption. It is also important to inform patients that bupropion hydrochloride tablets may cause mild pupillary dilation, which could lead to an episode of angle-closure glaucoma in susceptible individuals.

Patients should be made aware that bupropion hydrochloride tablets contain the same active ingredient as ZYBAN, which is used for smoking cessation, and that these tablets should not be used in conjunction with ZYBAN or any other medications containing bupropion. Furthermore, patients should be advised that any CNS-active drug, including bupropion hydrochloride tablets, may impair their ability to perform tasks that require judgment or motor and cognitive skills.

Patients must notify their healthcare provider if they are currently taking or plan to take any prescription or over-the-counter medications, as bupropion hydrochloride tablets may interact with other drugs. Additionally, patients should inform their healthcare provider if they become pregnant or plan to become pregnant while undergoing therapy with bupropion hydrochloride tablets.

Storage instructions should be provided, advising patients to keep bupropion hydrochloride tablets at room temperature, between 68°F and 77°F (20°C to 25°C), and to keep the tablets dry and protected from light.

Patients should be instructed to take bupropion hydrochloride tablets in equally divided doses three or four times a day, ensuring that doses are separated by at least six hours to minimize the risk of seizures. If a dose is missed, patients should not take an extra tablet to compensate but should take the next tablet at the regular time due to the dose-related risk of seizure. It is also important to instruct patients that bupropion hydrochloride tablets should be swallowed whole and not crushed, divided, or chewed, and that they can be taken with or without food.

Storage and Handling

The product is supplied in various package configurations, with specific NDC numbers available upon request. It should be stored at room temperature, ideally between 20° to 25°C (68° to 77°F). Temporary excursions are permissible within the range of 15°C to 30°C (59°F to 86°F).

It is essential to protect the product from light and moisture to maintain its integrity and efficacy. Proper handling and storage conditions must be adhered to in order to ensure optimal performance.

Additional Clinical Information

Patients receiving bupropion hydrochloride tablets for major depressive disorder (MDD) or other indications should be closely monitored by families and caregivers for signs of agitation, irritability, unusual behavioral changes, and suicidality. It is crucial for caregivers to report any concerning symptoms to healthcare providers immediately. Patients and their caregivers should be advised to discontinue bupropion and seek medical attention if they experience agitation, mood changes, or suicidal thoughts. Additionally, any neuropsychiatric symptoms such as delusions, hallucinations, or confusion warrant prompt consultation with a healthcare professional.

Patients should also be instructed to stop taking bupropion and contact a healthcare provider if they develop any allergic reactions, including skin rash or difficulty breathing. Postmarketing data indicate that serious neuropsychiatric events, including mood changes and suicidal ideation, have been reported in patients using bupropion for smoking cessation. Rare cases of severe skin reactions, such as erythema multiforme and Stevens-Johnson syndrome, as well as anaphylactic shock, have also been documented.

FDA Insert (PDF)

This document is the official FDA-approved prescribing information for Bupropion Hydrochloride as submitted by REMEDYREPACK INC.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)